The objective of the proposed studies is to generate an integrated understanding of the short-term and long-term control mechanisms which are involved in the regulation of fetal blood volume. The experiments will be conducted in the chronically catheterized fetal sheep. Improved techniques will be used to measure the volume of blood circulating in the fetus in utero. Four approaches will be taken to study the regulation of fetal blood volume: 1) blood volume restoration will be studied following slow and rapid fetal hemorrhage, 2) blood volume decrease will be determined as a function of severity of hypoxia, 3) volume transfer of fluid across the placenta will be determined during fetal or maternal hyperosmolality, and 4) long-term blood volume control will be determined during vascular volume loading or vascular volume depletion over a period of days. The mechanisms of the blood volume regulation will be explored for each of these studies by correlating the blood volume changes with changes in plasma protein concentration, red cell volume and vascular pressures as well as with changes in vascular compliance. Simultaneously, changes in fetal urinary output and tracheal secretion rate will be measured in order to examine the contribution of altered volume flows to fetal volume homeostasis. In addition the autonomic nervous and endocrine contributions to the volume regulation will be determined by measuring the rate and extent of volume adjustments in the presence and absence of catecholamine, angiotensin II, and arginine vasopressin receptor blockers. Overall, these studies are important not only because they will substantially expand our understanding of cardiovascular function in the fetus but also because they are relevant to several clinical problems including fetal hemorrhage, hypoxia, and edema as well as polyhydramnios. Thus the proposed studies may help provide a rational basis for therapeutic treatment of the unborn and the newborn and may therefore help decrease fetal and neonatal morbidity and mortality.